Synthesis of 20‐Membered Macrocyclic Pseudo‐Natural Products Yields Inducers of LC3 Lipidation

Abstract

Design and synthesis of pseudo‐natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP‐inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP‐macrocycles were synthesized efficiently in a stereoselective one‐pot procedure including the 1,3‐dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid‐derived azomethine ylides formed in situ. The 20‐membered bis‐cycloadducts embody 18 stereocenters and an additional fragment‐sized NP‐structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy‐related processes.

The Time and Place for Nature in Drug Discovery

“…Using the PNP algorithm, several PNP collections have been prepared over the past decade. By employing assays and subsequent follow-up biological characterizations, several PNP classes have been identified to be enriched in bioactivity that affect therapeutically relevant pathways, processes, and targets (Figure d). ,− The frequent success of the PNP algorithm suggests that it is a valid design principle for the exploration of biologically relevant chemical space.…”

Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space

“…[7][8][9] According to this design principle, NPs are deconstructed into fragments and recombined in arrangements that are not found in Nature to afford scaffolds that are NP-like but are not accessible via known biosynthetic pathways. The pseudo-NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10][11][12] or unprecedented bioactivities. [13] We describe the design and synthesis of a focused pseudo-NP collection comprised of two classes representing unprecedented scaffolds that occupy similar biologically relevant chemical space as MIA NPs (Figure 1b).…”

“…According to this design principle, NPs are deconstructed into fragments and recombined in arrangements that are not found in Nature to afford scaffolds that are NP‐like but are not accessible via known biosynthetic pathways. The pseudo‐NPs may inherit the biological relevance of NPs, however, their structures are not yet linked to bioactivity which may lead to the identification of unexpected [10–12] or unprecedented bioactivities [13] …”